One aspect of the invention is the preparation of .beta.-alkoxyacrylonitriles from metal salts of hydroxyacrylonitriles by transposition with halogen compounds.
The preparation of .beta.-alkoxyacrylonitriles according to the state of the art is difficult.
A complicated synthesis of .beta.-ethoxyacrylonitrile (I) by a plurality of steps has been described, which entails the tranposition of the sodium salt of .beta.-hydroxyacrylic acid ethyl ester with ethanol in the presence of HCl to form .beta.,.beta.-diethoxypropionic acid ethyl ester, the preparation of the amide by reaction with ammonia, and further dehydration with phosphorus pentoxide, .beta.-ethoxyacrylonitrile (I) being formed as a by-product (S. M. McElvain and R. L. Clark, J. Amer. Chem. Soc., 69, (1947) 2657).
In another, multiple-step synthesis, chloracetaldehyde is transposed with hydrocyanic acid to form .alpha.-hydroxy-.beta.-chloropropionitrile, which then reacts with acetic anhydride to form .alpha.-acetoxy-.beta.-chloropropionitrile. Pyrolysis of this compound leads to 33% .beta.-chloroacrylonitrile. This reacts with alkali alcoholates to form .beta.-alkoxyacrylonitrile (F. Scotti and E. J. Frazza, J. Org. Chem. 29, (1964) 1800).
.beta.-Ethoxyacrylonitrile can be prepared by the transposition of isoxazole with sodium hydroxide to the sodium salt of .beta.-hydroxyacrylonitrile and the alkylation of this compound in situ with diethyl sulfate or ethyl iodide (yield 37.6%). Isoxazole is obtained by the reaction of malonic dialdehyde acetal with hydroxylamine hydrochloride, so that the whole synthesis of .beta.-ethoxyacrylonitrile is accomplished only from very expensive chemicals and requires a plurality of synthesis steps (GB Pat. No. 806,235).
The present invention, therefore, has the object of preparing .beta.-alkoxyacrylonitriles in a simple manner and high yield by a method which is easy to practice on a technical and economical basis.
This object is accomplished in accordance with the invention by transposing an alkali or alkaline earth metal salt of .beta.-hydroxyacrylonitriles of the General Formula A with alkyl halides of General Formula B in the presence of a stabilizer and catalyst system to form a .beta.-alkoxyacrylonitrile of General Formula C. ##EQU3##
The subject matter of the invention is a method of preparing .beta.-alkoxyacrylonitriles of the formula EQU R'O--CH.dbd.CR--CN (C)
wherein R represents H, straight-chain, branched or cyclic alkyl moieties of 1 to 20 carbon atoms, straight-chain or branched moieties --(CH.sub.2).sub.n --CN, --(CH.sub.2).sub.n --OR" or --(CH.sub.2).sub.n --CH(OR").sub.2' wherein n=0 to 5 and R"=alkyl moieties of 1 to 12 carbon atoms, or --(CH.sub.2).sub.n+1 --Cyc, wherein Cyc represents isocyclic or heterocyclic mononuclear or polynuclear aromatic or cycloaliphatic ring systems having, in some cases, substituents on the rings, especially those of 5-8 carbocyclic carbon atoms per ring and n=0 to 5, and wherein R' represents straight-chain or branched alkyl or alkenyl moieties of 1 to 12 carbon atoms, isocyclic or heterocyclic mononuclear or polynuclear aromatic or cycloaliphatic ring systems, bearing substituents in some cases, especially those of 5-8 carbocyclic carbon atoms per ring, or --(CH.sub.2).sub.p --Cyc wherein Cyc has the same meaning as above, the moieties --(CH.sub.2).sub. p --OR'" or --(CH.sub.1 --CH.sub.2 --O).sub.q --R'" with p=1 to 5 and q=1 to 4 and R'"=straight-chain or branched alkyl moieties of 1 to 12 carbon atoms, which is characterized by contacting, at elevated temperature, a compound of the formula EQU (1/.alpha.Me)O--CH.dbd.CR--CN (A)
wherein R has the same meaning as above and Me is an alkali metal when .alpha.=1 or an alkaline earth metal when .alpha.=2, with a halogen compound of the formula R'--Hal(B), wherein R' has the meaning given above and Hal represents chlorine, bromine or iodine, in the presence of a basically reacting compound of the alkali or alkaline earth metals, as stabilizer.
The substituents R and R' are generally those which are inert with respect to the reactants. In the substituents R and R', those alkyl or alkenyl moieties which have 1 to 6 carbon atoms are preferred. Of the moieties containing cyclic ring systems, those which are mononuclear, i.e., monocyclic, are greatly preferred, and of those which are polynuclear the bicyclic are preferred.
In the polynuclear ring systems, the rings can be joined together directly by one or more atoms or they can be joined by means of one or more carbon atoms or heteo atoms as bridges.
The cycloaliphatic ring systems are preferentially cycloalkane moieties, but they may also contain one or more double bonds.
The heterocyclic moieties contain preferentially nitrogen, and in some cases also oxygen or other hetero atoms.
If there are to be substituents in the ring systems, they can be any substituents desired, provided they may be inert in the reaction. Preferred are lower alkyl groups of 1 to 3 carbon atoms, chlorine, or methoxy, ethoxy or carbalkoxy groups. Particularly contemplated mono and polycyclic rings are those derived from the following cyclic compounds phenyl, benzyl, naphthyl, disphenyl anilino, pyridyl, lower 1 to 3 alkyl pyridyl morpholino, piperidyl, lower 1 to 3 alkyl piperidyl and pyrrolidino.
The alkali or alkaline earth salts of .beta.-hydroxyacrylonitriles of General Formula A, which are used in preparing the .beta.-alkoxyacrylonitriles, can be prepared from alkyl cyanides, formic acid esters and alkali or alkaline earth alcoholates according to the principle of the Claisen ester condensation. A better method of preparing compounds of General Formula A, however, is described in German Patent Application No. P 27 53 322.8 and U.S. Application Ser. No. 963,713 filed Nov. 27, 1978, assigned to the assignee herewith, the disclosure which is hereby specifically incorporated herein by reference, in which alkyl cyanides are transposed with alkali or alkaline earth alcoholates in the presence of carbon monoxide. One can use the compounds of General Formula A prepared pursuant to this patent application directly, without further processing.
Sodium or potassium salts are preferred as alkali or alkaline earth compounds of Formula A on account of their easy accessibility. One can, however, use rubidium, cesium, magnesium or calcium salts.
The chlorine compounds are preferred as halogen compounds of Formula B, particularly methyl chloride, ethyl chloride, propyl chloride, isopropyl chloride, n-butyl chloride, isobutyl chloride, sec. butyl chloride, tert. butyl chloride, 2-methoxyethyl chloride, cyclohexyl chloride, allyl chloride, or benzyl chloride. The corresponding bromides or iodides can also be used, but they offer no advantage over the economically more attractive chlorides.
The halogen compounds are used in stoichiometric amounts or in an excess, preferably in a ratio of 1 to 2 moles of halogen compound per mole of compound of General Formula A. The excess halogen compound can be recycled.
A basically reacting compound of the alkali metals or alkaline earth metals is added to the reaction mixture as a stabilizing component, examples being alkali metal hydroxides, alkali hydrogen carbonates or alkali carbonates, as well as alkaline earth oxides, alkaline earth hydrogen carbonates or alkaline earth carbonates, such as NaOH, KOH, NaHCO.sub.3, KHCO.sub.3, Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, MgO, CaO, MgCO.sub.3 and CaCO.sub.3. CaO is used with preference.
The basically reacting compound is used in a ratio of 0.05 to 1 equivalent per mole of compound of General Formula A.
It is greatly preferred to use catalysts which increase the selectivity and speed of the reaction, consisting preferentially of quaternary ammonium salts of the formula: ##STR5## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 represent identical or, in some cases, different, linear or branched cycloalkyl, aryl, alkaryl, aralkyl or alkyl moieties of 1 to 20 carbon atoms, and X represents an univalent anion of an acid.
Of the cyclic moieties, monocyclic moieties are preferred, and of the aliphatic moieties those having 1 to 6 carbon atoms are preferred.
Examples of R.sup.1 to R.sup.4 are methyl, ethyl, propyl, butyl, octyl, cetyl, benzyl or phenyl. Examples of anions are fluoride, chloride, bromide, iodide, hydrogen sulfate, hexafluorophosphate, cyanide, azide, nitrate, nitrite, perchlorate, tetrafluoroborate, cyanate, thiocyanate, trifluoromethanesulfonate, 4-toluenesulfonate and hexafluoroarsenate. A preferred compound is tetra-n-butylammonium chloride, bromide or iodide.
The crown ethers that can be used instead of the quaternary ammonium salts are cyclic ethers of glycols in which the numbers indicate the number of glycol groups. They are, for example, 15-crown-5, 18-crown-6, dibenzo-18-crown-6 and dicyclohexyl-18-crown-6* FNT *(see F. Vogtle and E. Weber: "Kontakte" 1977, 1 p. 11; 1977, 2, p. 16; 1977, 3 p. 36 published by Merck Comp. Germany)
The quaternary ammonium salt of General Formula D or of the crown ethers are used in catalytic amounts with respect to Compound A. In general, 10.sup.-3 to 10.sup.-1 moles of quaternary ammonium salt or crown ether are used per mole of compound A. Higher concentrations are possible, but economically undesirable.
An iodine compound can be added to the catalyst. One can use, therefor, a substance consisting of an iodide or a compound giving off iodine ions under the reaction conditions. By this means the highest reaction rates and best yields are generally achieved. For example, the quaternary ammonium salt of General Formula O can be added in the form of an iodide. It is furthermore possible to add to the alkyl halide of General Formula B small amounts of the corresponding iodide. An inorganic salt with an iodide anion can be added. For example, LiI, NaI, KI, CuI, ZnI.sub.2 or CoI.sub.2 can be used. The iodine compound is added in a ratio of 10.sup.-3 to 10.sup.-1 moles per mole of compound of General Formula A.
Aprotic solvents are appropriate. For example, alkanes, benzene or toluene are solvents of the hydrocarbon series which can be used. Ethers can be used, such as tetrahydrofuran, dimethoxyethane, and di-, tri- or tetraglymes. Polar aprotic solvents, such as hexamethylphosphoric acid triamide, dimethylsulfoxide, dimethylformamide or acetonitrile are also good solvents for the reaction. The process can be operated with or without the use of solvents.
The solvents can be used in quantities of 0.5 to 2 liters per mole of the compound of General Formula A. Larger amounts of solvent are possible, but offer no advantage.
A temperature range of 60.degree. to 220.degree. C. has proven to be a desirable one for the reaction. Particularly when chlorine compounds are used as the halogen compounds of Formula B, it is advantageous to keep the reaction temperature in the range from 80.degree. to 180.degree. C., in order to achieve sufficiently rapid reactions. The reaction time is between 1 and 8 hours, depending on the reaction temperature, during which a complete transformation of Compound A is achieved.
The reaction can be preferred at standard pressure, at reduced pressure or at excess pressure up to 50 atmospheres. Higher pressures are possible but not desirable. Preferably the pressure is between standard (atmosphere) pressure and the self pressure of the reactants.
The reaction can be performed as follows: The starting substance A, together with the basically reacting inorganic salt, the quaternary ammonium salt, and the iodine compound if used, dissolved or suspended in the solvent, is placed under inert gas in a reactor provided with a stirrer. Then starting substance B is added, and the reactor is closed and raised under the self-pressure to the reaction temperature. After the reaction has ended, the reactor is cooled and vented, and the reaction mixture is taken out. The solid is separated by filtration or centrifugation, and the end substance C is isolated, for example by fractional distillation.
.beta.-Alkoxyacrylonitriles are valuable starting substances for the preparation of heterocyclic compounds. For example .beta.-alkoxyacrylonitriles of the Formula ##STR6## can be reacted with urea to form cytosine derivatives substituted in 5-position (G.B. Pat. No. 806 235): ##STR7## Cytosin and its derivatives can be used as anti-tumor drugs (Belgian Pat. No. 74 74 76) agrochemicals (Japanese published Application No. 65-68 113) or as photochemicals (German Pat. No. 25 06 320).